Issue 24, 2021

Semisynthetic ‘designer’ p53 sheds light on a phosphorylation–acetylation relay

Abstract

The tumor suppressor protein p53 is a master regulator of cell fate. The activity of p53 is controlled by a plethora of posttranslational modifications (PTMs). However, despite extensive research, the mechanisms of this regulation are still poorly understood due to a paucity of biochemical studies with p53 carrying defined PTMs. Here, we report a protein semi-synthesis approach to access site-specifically modified p53. We synthesized a set of chemically homogeneous full-length p53 carrying one (Ser20ph and Ser15ph) or two (Ser15,20ph) naturally occurring, damage-associated phosphoryl marks. Refolding and biochemical characterization of semisynthetic p53 variants confirmed their structural and functional integrity. Furthermore, we show that phosphorylation within the N-terminal domain directly enhances p300-dependent acetylation approximately twofold, consistent with the role of these marks in p53 activation. Given that the p53 N-terminus is a hotspot for PTMs, we believe that our approach will contribute greatly to a mechanistic understanding of how p53 is controlled by PTMs.

Graphical abstract: Semisynthetic ‘designer’ p53 sheds light on a phosphorylation–acetylation relay

Supplementary files

Article information

Article type
Edge Article
Submitted
21 Janv. 2021
Accepted
18 Maijs 2021
First published
19 Maijs 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021,12, 8563-8570

Semisynthetic ‘designer’ p53 sheds light on a phosphorylation–acetylation relay

S. Margiola, K. Gerecht and M. M. Müller, Chem. Sci., 2021, 12, 8563 DOI: 10.1039/D1SC00396H

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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